Most antiviral therapeutic compounds block various specific viral genetic replicative mechanisms within infected target cells. These approaches have drawbacks including toxicity to host cells, induction of drug-resistant viral sub-strains, and the potential to act as mutagens and/or teratogens for host cells. Consequently, the search for new antiviral compounds that will provide efficacious therapy, without such deleterious consequences to the host, is of paramount importance. This is particularly true as we appear to enter a new age of vulnerability to heretofore obscure viruses of the retroviral family.
Compounds that exert antiviral activities without being potentially detrimental to the infected host have been identified and have shown some promising results. In the late 1970's, for example, Snipes and colleagues (W. Snipes, S. Person, G. Keller, W. Taylor, A. Keith, Antimicrob. Agents Chemother. 11, 98-104 (1977); J. Sands, D. Auperin, W. Snipes, Antimicrob. Agents Chemother. 15, 67-73 (1979)) reported a series of studies demonstrating such activities for both saturated and unsaturated alcohols of moderate chain lengths. Optimal antiviral activity was observed with 10-12 carbon-long saturated alcohols; less antiviral activity was observed with alcohols 14-18 carbons long, and alcohols of higher chain lengths were not tested. While significant antiviral activity was observed with C-10 and C-12 alcohols, these compounds also exhibited cytotoxic and hemolytic effects. Similar observations were made with unsaturated alcohols and monoglycerides, peak activity occurring with C-18 alcohol containing three double bonds. Subsequently, Clark and colleagues (L. L. Clark, Treatment for inflammatory skin disease. U.S. Pat. No. 4,670,471 (1987); P. T. McBride, L. L. Clark, G. G. Krueger, J. Invest. Dermatol. 89, 380-383 (1987)) concluded that the 30 carbon-long saturated alcohol, triacontanol, was active as an anti-herpes agent. However, since tissue culture studies demonstrated that triacontanol lacked direct antiviral activity, it was speculated that the apparent anti-herpes activity observed in animal studies might reflect a putative immunomodulatory effect of this compound.
As early as 1974, n-docosanol was reported to have systemic therapeutic value. For example, Debar, U.S. Pat. No. 4,186,211, reported that 1-docosanol when taken orally was therapeutically effective in the treatment of enlargement of the prostate gland. Similar work was reported a decade later by Yamamoto, et. al, e.g. U.S. Pat. No. 4,624,966, who, incorrectly as to chemical nomenclature, listed n-docosanol as a polyprenyl compound and described the peroral or parenteral administration of n-docosanol in therapy. Neither Debat nor Yamamoto, et. al, nor any other workers, have, to the knowledge of the present inventors, suggested even remotely, the possibility that n-docosanol might be an active agent in topical therapy.
After examining the results of Snipes and colleagues, and realizing that compounds longer than 18 carbons had not been examined to ascertain if they might exhibit topical antiviral or inflammatory activity, we reasoned that a molecule twice as long as C-10 or C-12 (which had displayed peak antiviral, but also cytotoxic and hemolytic activity) might retain biological activity against viruses, but (perhaps because of folding-over of the molecule) lack the hemolytic and cytotoxic property of the shorter molecule. Studies in our laboratory testing the antiviral properties of n-docosanol were favorable (Katz, D. H., U.S. Pat. No. 4,874,794).
The preparation of stable, efficacious n-docosanol-containing topical formulations, however, presented a challenge. While creams and ointments of certain conventional formulation were initially adequate for preliminary evaluations, we found that certain excipients were detrimental to the activity of n-docosanol. It became obvious, therefore, that there was a need for reproducibly effective formulations of n-docosanol that were stable for long periods of time, physiologically acceptable and suitable for topical application to skin and membranes. The preparation of stable, effective n-docosanol-containing compositions presented an unexpectedly difficult challenge. Conventional cream formulations that are entirely suitable for preparing carrier creams for most pharmaceuticals were not satisfactory. While penetration enhancing compounds were considered as possibly desirable, increasing penetration enhancement was not a particular problem. Many penetration enhancers are available but there was no reason to consider such materials vis-a-vis penetration enhancement and certainly no reason to expect that any of these materials would result in a cream that would result in enhanced pharmaceutical efficacy and would be stable at all temperatures such a product would encounter during storage and handling, and for all time periods that would expected in normal storage and handling and, in addition, be stable through phase changes and/or being exposed to temperatures well below the freezing point of the aqueous constituent of the cream and in which the highly hydrophobic long chain alcohols of this invention would retain pharmacological activity. Azone, reported by Rajadhyaksha, for example, is an excellent penetration enhancer but has not been known as a stabilizing constituent in cream formulations. Sucrose esters of coconut fatty acids have been formulated as penetration enhancers, Cheng. et. al., U.S. Pat. No. 4,865,848, and other patents. Cheng, et. al., do not suggest, however, any cream stabilization resulting from these materials, nor is there any reason to infer such stabilization from the Cheng, et. al. patents. Literature on such compounds does not suggest these materials as being particularly effective in stabilizing C-20 to C-28 aliphatic alcohol-containing creams. It is to the solution of these problems that this invention is directed. Specifically, this invention is directed to an efficacious, stable, physiologically acceptable cream suitable for topical application of C-20 to C-28 aliphatic alcohols, e.g. n-docosanol, for therapy.
A variety of formulae compositions were experimentally tested as to stability and providing a cream in which the long chain alcohols exhibited high physiological activity in a topical cream. Some formulations exhibit poor stability and some exhibited poor physiological activity. Only the formulations that are the subject of this invention were found to be satisfactory as to stability and activity.
One significant result came as a complete surprise--the immediate reduction and sometimes complete relief from the pain of inflammation of the skin and mucous membranes.